It is well known that both negative energy balance and muscle catabolism are consequences of physiological stress that often accompanies protein calorie malnutrition, strenuous physical exercise, physical trauma, burn injury, surgical trauma, malnutrition, maldigestion, malabsorption, hyperthyroidism, chemotherapy, radiation therapy, anorexia, cachexia, short bowel syndrome, old age, sepsis and other conditions. It is also known that maintaining a positive metabolic energy balance can help to alleviate such problems and also has a sparing effect on muscle catabolism that occurs during strenuous physical exertion causing fatigue.
Athletes, in particular, have needs for maintaining and/or building muscle mass compatible with their genetic makeup to optimize their strength, body tone and physical abilities. Ideally, this would be accomplished using the body's own resources without being subjected to the administration of anabolic steroids and the associated negative side effects.
It is well known that anabolic steroids, such as testosterone and natural and synthetic derivatives and substitutes, affect many metabolic activities such as muscular development and fat distribution. Administration of anabolic steroids tend to take users past their natural or genetic limits to create body size and muscle mass beyond that which is optimal to the genetic makeup of the individual and past that which can be effectively supported by the various organs of the body.
Excess anabolic steroids tend to suppress or dam up other natural, yet essential, hormones in the body such as the andrenocorticosteroids. The glucocorticoids, and cortisol (hydrocortisone) in particular, are necessary in the metabolism of carbohydrates and fats. Cortisol promotes gluconeogenesis by peripheral and hepatic actions. It acts to mobilize proteins and amino acids from skeletal muscle. Proteins and amino acids funnel into the liver, where they engage the enzyme systems involved in the production of glucose and glycogen. In quantitative terms, the peripheral action of cortisol accounts in large measure for its gluconeogenic effect. In the liver, especially on a long term basis, cortisol induces the synthesis of a number of enzymes intimately involved in gluconeogenesis.
However, release or administration of large doses of cortisol can produce changes in carbohydrate, protein and fat metabolism. Blood sugar tends to be high, liver glycogen is increased and there is increased resistance to insulin. The catabolic action of cortisol is reflected in the wasting of tissues, reduced mass of muscle, osteoporosis and thinning of the skin. In certain instances, a diabetic-like state may be produced.
Excess amounts of cortisol also causes an alteration in fat distribution. There is a gain of fat in depots in the neck, supraclavicular area and cheeks and a loss of fat from the extremities.
Elevated cortisol levels are also known to suppress the immune system. Cortisol prevents glucose entry into muscle and adipose tissue and decreases activity of insulin. Moreover, cortisol has been shown to inhibit LH release in the bovine species and therefore has an effect on reproduction. Insulin availability may limit the onset of ovarian activity in the female leading to ovulation. Insulin is also known to reduce concentration of blood ketone bodies. Sartin et al., Plasma Concentrations of Metabolic Hormones in High and Low Producing Dairy Cows, J. Dairy. Sci. 71:650-657, 1988 reports that cortisol is antagonistic to milk production.
Chromium has been shown to suppress the production of glucocorticoids. Chromium functions as a potentiator of insulin. Chromium is a trivalent mineral which has been found in recent years to be more bioavailable when administered as an organic complex. The most common organic complex is a low-molecular weight organic complex termed "glucose tolerance factor" (GTF) obtained primarily from Brewer's yeast. Recent research has shown that various stressors such as infection, strenuous exercise, pregnancy, change of environment, etc, increase urinary excretion of chromium. Sub-optimal levels of chromium may be a factor in several stress related diseases. Schnauzer et al., Effects of Chromium Supplementation in Food Energy Utilization and the Trace-element Composition in the Liver and Heart of Glucose-exposed Young Mice, Biol. Trace Element Res. 9:79 1986, have shown that chromium supplementation protects against stress-induced losses of trace minerals such as zinc, copper, iron and manganese. Polansky et al., Beneficial Effects of Supplemental Chromium on Glucose, Insulin and Glucagon of Subjects Consuming Controlled Low Chromium Diets, FASEB J. A2964. 1990, report that human dietary chromium intakes is suboptimal with diets of approximately twenty-five percent of the U.S. population containing forty percent or less of the recommended daily chromium intake. There is also evidence that chromium in the human body decreases with age. In the animal kingdom, it has been found that steers, subjected to conditions of stress, have increased serum cortisol levels which can be lowered by administration of supplemental chromium.
Moreover, chromium is an essential trace element as a cofactor in several enzyme systems. As mentioned above, it is associated with a low-molecular weight organic complex termed "glucose tolerance factor" (GTF) that acts with insulin in promoting normal glucose utilization. Brewer's yeast, which is rich in GTF, has been shown to improve glucose tolerance, lower serum cholesterol and triglycerides in some subjects and to reduce insulin requirements in some diabetics. Glucose tolerance is usually impaired in protein-calorie malnutrition and some cases have shown a dramatic response to administration of trivalent chromium. Deficiency has been reported in patients on prolonged parenteral feeding. Additionally, GTF is not only a co-factor of insulin thus influencing glucose, but protein and lipid metabolism as well. GTF is not as effective, if not ineffective, in the absence of insulin. The exact mechanism by which GTF improves glucose tolerance is not known. However, it is thought that GTF enhances the binding of insulin to its specific receptors.
Another part of the beneficial effects of chromium on the immune system may be related to vitamin C metabolism. It is known that cattle arriving at a feedlot in a chronically stressed condition show evidence of hyperglycemia and are at greater risk of disease as vitamin C entry into neutrophils is most likely reduced. Vitamin C is needed for neutrophil function, decreases circulating corticoid levels and ameliorates immunosuppression in stress. Nockels, Effect of Stress on Mineral Requirements, Western Nutritional Conference, 1990 and Satterlee et al., Vitamin C Amelioration of the Adrenal Stress Response in Broiler Chickens Being Prepared for Slaughter, Comp. Biochem. Physiol., 94A:569-574, 1989 have shown that vitamin C ameliorates the negative effect of stress in broiler chickens being prepared for slaughter which is possibly due to suppression of adrenocortical steroidogenesis. Synthesis of ascorbate from glucose may be reduced when glucose is deficient as in earlier fasting during transport. Calves may also have a low glucose synthesis when fed forage diets so vitamin C synthesis may be low.
Glucocorticoids are known to suppress the immune system according to Munck et al, Physiological Functions of Glucocorticoids in Stress and Their Relation to Pharmacological Actions, Endoc. Rev. 5:25, 1984. Therefore, another beneficial effect of chromium supplementation during periods of stress in suppressing cortisol serum levels could conceivably result in improving effectiveness of certain vaccines. Carlson et al., The Bovine Proceedings, 15:84 1990, measured antibody response to IBR vaccination in feedlot cattle found cattle to be poorly responsive to immunization upon arrival in the feedlot. These results were attributed to the stresses of shipping and respiratory infection drawing the conclusion that such factors may render an animal immunoincompetent.
Supplemental chromium, administered to bovine species, has been shown to decrease serum cortisol and may increase milk production. Supplemental chromium has also has been found to be associated with weight gain in stressed animals. Part of the improvement in gain with administering supplemental chromium may be due to decreasing cortisol production. It has been shown by Southorn et al., The Effect of Corticosterone Treatment of the Response of Muscle Protein Synthesis to Insulin Infusion in the Rat, J. Endocrin. 23: abst. #127, 1989, that rats treated with corticosterone developed insulin resistance with respect to muscle protein synthesis. Clinical evidence supports the immunosuppressive activity of glucocorticoids through impairment of neutrophil function and suppression of lymphocyte blastogenesis.
However, once chromium is mobilized in the body in response to increased glucose metabolism, elevated insulin response, stress, elevated cortisol levels, etc., it is not reabsorbed in the tissues but is excreted in the urine. Therefore, diets and/or conditions that lead to chromium utilization also lead to chromium depletion. Sufficient chromium supplementation, in a bioavailable form, is therefore essential to the proper functioning of the metabolic system.
Magnesium is the fourth most abundant cation in the body. Almost half of the magnesium in the body is located in the bone. Of the non-osseous tissues, liver and striated muscle have the highest magnesium concentrations. Magnesium is an activator of a host of enzyme systems that are critical to cellular metabolism. Prominent among these are the enzymes that hydrolyze and transfer the phosphate groups, e.g. the phosphatases and those concerned in the reactions involving adenosine triphosphate (ATP). Since ATP is required for glucose utilization, fat, protein, nucleic acid and coenzyme synthesis, muscle contraction, methyl group transfer, sulfate, acetate and formate activation, by inference the activating effect of magnesium extends to all these functions. One means by which magnesium is involved in protein synthesis is by contributing to the binding of messenger RNA to the 70S ribosome. Magnesium is also required for the synthesis and degradation of DNA and has also been included in all the amino acid activating systems.
By means of one or more of the above mechanisms, magnesium is essential to the building of maximum muscle mass and endurance. Strenuous physical activity and associated mental and physical stress can cause a decline in tissue magnesium levels as a result of hypermetabolic compensation and the increased elaboration of catecholamines, glucagon, and mineral corticoids. Magnesium administered in the form of inorganic salts to replenish reduced levels in the body, can cause serious side effects such as intestinal irritability, loose stools, or diarrhea. Because of this, many body builders or other athletes are magnesium deficient and sufficient levels of magnesium are not included in many prior art anabolic formulas. It is therefore essential that any magnesium administered is in a safe but effective bioavailable form. One such form which has been shown to be superior to all others is as an amino acid chelate.
There are certain amino acids that affect the positive balance of nitrogen in the building or synthesis of skeletal or muscular proteins. These function in the presence or absence of insulin but have a greater response in the presence of insulin. Glutamine, glycine and arginine are all anabolic and also all have well-defined metabolic behaviors that are distinct from their participation in protein synthesis and breakdown. According to Rennie et al., J Nutr. 124: 1503S-1508S (1994) it has been found that there is a strong relationship between the rate of muscle protein synthesis and intramuscular glutamine concentration. Rennie et al. state that there is little doubt that the phenomenon of an anabolic effect of glutamine in human and animal muscle exists, however, the nature of the mechanism is not evident. Glutamine or L-glutamine, not only has a positive effect on the nitrogen balance in protein, i.e. is anabolic, but also stimulates the accumulation of muscle glycogen in rats. It is suggested that any processes that interfere with the ability of muscle to accumulate glutamine will result in muscle wasting and therefore, the effects of disease and injury causing muscle wasting may include interference with the muscle glutamine transporter.
Young et al, J. Parenteral and Enteral Nutrition, 17: 422-427 (1993) states that glutamine has been shown to be clinically safe when administered as a supplemental nutrient and improves nitrogen balance. It is also known that glutamine is a precursor of the neurotransmitter .tau.-aminobutyric acid and can cross the blood-brain barrier. Glutamate, which is a product of glutamine metabolism, and vice versa, is the most abundant single amino acid within the central nervous system and also functions as a neurotransmitter. Because of this property, Young et al., have found that glutamine also possesses antidepressive properties.
According to Gore, et al., Arch. Surg. 129:1318-1323 (1994) catabolic hormones, such as cortisol, increases the efflux of glutamine resulting from an accelerated release of glutamine from the free intracellular glutamine pool that is then replenished from either increased endogenous protein breakdown or from de novo glutamine synthesis. This is further indication that increased cortisol has an adverse or catabolic affect on the nitrogen balance of muscle tissues and also of the need for a source of bioavailable glutamine.
To permit optimal muscle growth and maintenance, it is essential that a proper balance be maintained between endogenous anabolic steroids and cortisol such that these hormones are present in amounts sufficient to enable the various body processes to function normally while, at the same time, minimizing the adverse side effects caused by these same hormones. It is also necessary that adequate amounts of chromium and magnesium, in a bioavailable form, are present to regulate enzyme functions, cortisol levels, and optimize synthesis of proteins, glucose, and fat distribution.
Ashmead et al., U.S. Pat. No. 4,020,158; Ashmead, U.S. Pat. No. 4,076,803; Jensen U.S. Pat. No. 4,167,564; Ashmead, U.S. Pat. No. 4,774,089 and Ashmead, U.S. Pat. No. 4,863,898 all disclose metal amino acid chelates and various uses for these chelates in reference to increasing absorption of essential minerals into biological tissues. Some of these patents suggest that certain mineral and ligand combinations can enhance metal uptake in specific organs or tissues where specific biological functions are enhanced, i.e. minerals crossing the placental membranes into foeti, estrus or spermatogenesis, etc.
However, although amino acid chelates and some of the uses to which they are applicable are documented in the art, there is no teaching or suggestion that proper formulations and administration of a chromium salt, complex or chelate, in combination with a specific magnesium amino acid chelate (magnesium glycyl glutaminate) can have an anabolic effect in the building and maintaining of muscle mass in a manner which equals or is superior to the administration of anabolic steroids but without having the negative side effect.
It would be desirable to enable the building of muscle mass and strength in a manner consistent with the genetic makeup of an individual without resorting to the use of substances, natural or synthetic, which have a negative physiological impact. It would also be desirable to optimize such building of muscle mass using nutritional supplements which awaken the inherent processes of the body to function at peak natural performance for that particular individual.